The goal of this proposed program is to develop new and broadly useful synthetic methods and strategies and apply these to preparing biologically active alkaloids and other nitrogen containing compounds that serve as potential leads for developing novel therapeutic agents. The specific objectives fall into the categories of methodological studies and total synthesis. In the arena of synthetic methodology, we will develop: (1) new tactics to prepare y-ylidenetetronates, key subunits in biologically active compounds;(2) new procedures for generating and reacting azomethine, carbonyl and thiocarbonyl ylids as a novel entry to nitrogen, oxygen and sulfur heterocycles;(3) new protocols for enantioselective introduction of functionalized alkyl substituents onto electron rich heterocycles and aromatic rings;and (4) new means for effecting diastereoselective, oxidative rearrangements of indoles to oxindoles. In the arena of target directed synthesis, we will: (1) develop the first enantioselective route to didehydrostemofoline, a novel alkaloid having potent anticancer and anti-oxytocin activity;(2) complete the first synthesis of (-)-/V- methylwelwitindolinone C isothiocyanate, an unusual alkaloid that reverses multiple drug resistance in cancer cell lines;and (3) complete the first synthesis of (-)-citrinadin A, an unusual pentacyclic alkaloid that exhibits promising anticancer activity. The synthetic routes to each of the natural products has been uniquely designed so analogs may be easily prepared to conduct critical SAR studies that will establish some essential features for optimal biological activity. Derivatives of the natural products and selected synthetic intermediates will be submitted to Abbott Laboratories and Merck Research Laboratories for biological evaluation for anticancer activity. Two aspects of the proposed research are critical to public health. Firstly, the new methods for synthesizing heterocycles having diverse structures will be of great use to chemists in the pharmaceutical industry in their efforts to identify new drug candidates. Secondly, the synthetic targets we have identified have significant potential as leads for the development of novel anticancer agents.